Results: Sle2 synergized with lpr, resulting in a greatly accelerated lymphadenopathy that largely targeted T cells and mapped to the Sle2c1 locus. This locus has been identified as the main contributor to B-1a cell expansion. Further analyses showed that Sle2c1 expression skewed the differentiation and polarization of Fas-deficient T cells, with a reduction of the CD4+CD25+FoxP3+ regulatory T-cell subset and an expansion of the Th17 cells. This was associated with a high number of T-cell infiltrates that promoted severe nephritis and dermatitis in the B6.Sle2c1.lpr mice.
Conclusion: These results show that Sle2c1 contributes to lupus pathogenesis by affecting T-cell differentiation in combination with other susceptibility loci, such as lpr. The significance of the cosegregation of this phenotype and B-1a cell expansion in Sle2c1-expressing mice in relation to the pathogenesis of lupus is discussed.
The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice. (Arthritis Rheum. 2011;63:1076-1085.)
Abstract
Objective: Complement has both protective and pathogenic functions in lupus due to a balance between its role in the clearance of immune complexes (ICs) and apoptotic cells and its role in inflammation. The classical pathway contributes to IC and apoptotic cell clearance, whereas the alternative pathway is a key mediator of renal inflammation. The aim of this study was to investigate the effect of a new targeted inhibitor of the alternative pathway, CR2-fH, on lupus-like renal disease in MRL/lpr mice.
Methods: Mice were treated with either saline, CR2-fH, CR2-Crry (which inhibits all complement pathways), or soluble CR2 (sCR2; C3d-binding targeting vehicle). Sera were analyzed every 2 weeks for autoantibodies, circulating ICs, and C3. Urinary excretion of albumin was also determined, and kidneys were collected at 23 weeks for histologic evaluation.
Results: Treatment with CR2-fH or CR2-Crry improved survival and significantly reduced proteinuria, glomerular C3 deposition, and the level of circulating ICs. CR2-fH, but not CR2-Crry, also significantly reduced glomerulonephritis, expression of serum anti–double-stranded DNA (anti-dsDNA) antibodies, and glomerular IgG and C1q deposition. Interestingly, sCR2 also significantly reduced the levels of anti-dsDNA antibodies and circulating ICs and reduced glomerular deposition of IgG, C1q, and C3, although there was no significant reduction in glomerulonephritis, proteinuria, or mortality.
Conclusion: Targeted and selective inhibition of the alternative complement pathway is an effective treatment of murine lupus and is more effective than blockade of all pathways. The data demonstrate benefits to leaving the classical/lectin pathways intact and indicate distinct roles for the classical and alternative pathways of complement in disease progression. The sCR2-targeting vehicle contributes to therapeutic activity, possibly via modulation of autoimmunity.
